Preparation of sulphanilamide derivatives



Paten ted-Oct. 14, 1941 e UNITED STATES PATENT OFFICE raarnaarron or 8mm DERIVATIVES s Arthur James Ewins, Gidea Park, Romiord, and

Montague Alexander Phillips, Romtord, England, assignors to May & Baker, Limited, London, England, a company of Great Britain.

No Drawing. Original application November 1,

1938, Serial No. 238,164.

Divided and this application April 19, 1940, Serial No. 330,527. In Great Britain, Australia, India, and New Zealand November 29, 1937 2 Claims.

This is a division of co-pending application Ser. No. 238,164, filed November 1,.1938, for The preparation of new therapeutically useful heterocyclic compounds."

The present invention relates to the prepara- .tion of p-amino-benzene-sulphonamido derivatives of the pyridine, quinoline and isoquinoline series, many of which have marked bactericidal properties and are capable of therapeutic application.

The compounds prepared according to the present invention are of the type in which R represents a heterocyclic nucleus of the pyridine, quinoline or isoquinoline series. and-- inwhich R1 may be hydrogen, acyl, alkyl, aryl or aralkyl, and R2 may be hydrogen or allgvl and R3 may be hydrogen, alkyl, aryl, aralkyl or acyl,

According to the present invention these compounds may be prepared by various methods which may be summarised as follows:

A. Derivatives in which R1, R2 and R: are hydrogen atoms may be prepared by condensing a compound of the type p-X CcH4Y with a compound of the type ZR in which R. is a pyridine, quinoline or isoquinoline residue, and when Y is 50201, X is NHz and when Y is SOzNH: Z is a halogen, to form compounds of the type x CsH4SO2NHR or aralkyl group may be-prepared by condensing a compound of the type R1RaN.CsH4Y with a compound or the type ZR. in which R is the resi-' due of a pyridine, quinoli'ne or isoquinoline base,

and when Y is SOaCl, Z is NHRa and SO2NHR3, Z is a halogen. v

D. Derivatives inwhich R1 is a hydrogen or alkyl, R2 is an alkyl, and R: is hydrogen or an alkyl, aryl or aralkyl group may be prepared when Y is from condensation products 0! the types described in A and B in which X is a halogen by reacting on the respective halogenated condensation products with a primary or secondary amine instead of with ammonia.

E. Acyl, alkyl, aryl or aralkyl derivatives of compounds prepared by the foregoing methods containing oneor more replaceable hydrogen atoms attached to nitrogen may be prepared by known methods such as by the use of acyl', alkyl,

aryl, or aralkyl halides or alkyl sulphates. Besides using compounds or the type various chemically equivalent processesmay be' used instead, such as the use of the anhydrides (p-XCsHrSOzhO or the bromides which can be readily converted into compounds I of the type NH2CeH4SO2NI-IR. X therefore represents a group such as an acylamino group, a

nitro group, an azo group linked to an organic gen to form compounds of the type from which the required amino products may be obtained as described in paragraph A.

C. Derivatives in which R1 is hydrogen or an alkyl or acyl group, R2 is an alkyl, aryl, or aralkyi group and R: is either hydrogen or an alkyl, aryl, 55 tion in normal sodium hydroxide solution with cooled and made just acid to litmus by addition The following examples illustrate how the in ventlon may be carried out in practice, but it is to be understood that the invention is in no way limited to the details given in these examples:

Example 1 2-amino-pyridine (9.4 grams) is dissolved in 20 cc. of dry pyridine and 23.5 grams of p-acetylamlno-benzene-sulphonyl chloride is added and the mixture heated on the steam bath. Water is then added and the precipitated 2-(p-acetylamino-benzene-sulphonamido) pyridine, M. Pt, 224 C., hydrolysed by boiling with cc. of 2N sodium hydroxide solution. The solution is of 2N hydrochloric acid. The precipitate oi 2-(p-amino-benzene-sulphonamido) -pyridine is collected andrecrystallised from water. Melting point 190 C.

a Example 2 To 16 grams'oi' G-amino-quinaldine dissolved in 30 cc. of dry pyridine is added 24 grams oi p-acetyiamino-benzene-sulphonyl-chloride. After heating on a steam bath for 1 hour and diluting Y with water, the crystalline precipitate is collected,

washed and purified by precipitation 01' the soluformed.

excess of boiling 2N acetic acid. It melts at This is converted to the amino compound by refluxing for 30 minutes with ten times its weight of 2N sodium hydroxide solution. On acidification to litmus, the base is obtained as a gum which rapidly crystallises. Alternatively, hy-

drolysis may be effected by heating under reflux with 12 parts of dilute 15% hydrochloric acid for 1 hourand adding 50% sodium hydroxide solution until the solution is still acid to litmus but not to Congo red. The precipitated product is purified by solution in' boiling alcohol andprecipitation with water. Melting point 252 C. Example 3 Tea solution of 4.7 grams of 2-amino-pyridine in 10 cc. of dry pyridine is added, with cooling, 12 grammes of p-nitro-benzene-sulphonyl-chloride. An energetic reaction results: when this is over, the mixture is diluted withwater, (200 cc.) and the precipitate of- Z-(p-nitro-benzenesulphonamido) -pyridine collected. Melting point 185 C. e

The nitro compound (1.4 grams) is dissolved in about cc. of 2N sodium'hydroxide solution and thesuspension of Na salt formed on standing is added at 20C. to a paste of ferrous hydroxide from grams ferrous sulphate (hydrated) in 30 cc. water and3 grams sodium hydroxide in 5 cc. of water. After standing (1 hour) the mixture is filtered from ferric hydroxide and the filtrate acidified with acetic acid. The 2-(pv amino-benzene-sulphoriamido) -pyridine melts .at

Example 4 16.5 grams of p-chlorobenzene-sulphonyl-chloride is added ,to a solution of 7 grams of 2-aminopyridinein cc. of pyridine. After heating at 90 C. for 15 minutes, water is added and the precipitated 2- (p-chlorobenzene-sulphonamido) pyridine is collected; washed anddried, M. Pt.

With4 parts by ,weight of concentrated aqueous ammonia in the presence of about 35 part by weight of cuprous chloride for 13 hours at 150- 175 OJ The excess of ammonia is removed and on dilution with water,- 2-(p-amino-benzene-sulphonamido) -pyridinje is obtained a'ndmay be purified by crystallisation from water.

Example 7 5 A mixture of 21.4 grams of Y p-acetylaminobenzene-sulphon-amide, 13.0 grams of anhydrous potassium carbonate, 1.0 gram of, copper powder and. 15.8 grams of 2-bromo-pyridine is heated at 200-240 for 1 hour. The'melt'is' dissolved in boiling water and filtered. Onacidification with acetic acid, .2- gp-acetylaminobenzene-sulphonamido)-pyridine. M. 'Pt. 224 is obtained from which 2-(p-amino-sulphonamidoi-pyridine is formed by alkaline hydrolysis.

Example 6 10 trains of p-nitro-benzene siflphonic acid anhydride (prepared bythe action oi thionyl chloride on p-nitro-benzene-sulphonic acid dihydrate) are added to a solution of 5 grams of.

2-a nino-pyridine in 25 cc. of pyridine. The reaction mixture becomes warm and a precipitate of 2? (p-niti'o-benzene-sulphonamido) -py 1d1ne is water and dried. 'Melting point 195 c This compound on reduction according to th e reaction mixture is diluted with- 186 C. This is then heated in a closed vessel 1 acetyl-amino-benzene-sulphonamido) method of Exainple 3 yields 2-(p-amino-benzenesulphonamido) -pyridine.

Example 7 2.5 grams of 2-(p-amino -benzene sulphonamido)-pyridine is suspended in 10 cc. of pyridine at laboratory temperature and 2 grams p-nitro benzoyl chloride is added. The mixture is allowed to'cool, diluted with water, and the precipitated 2-[p-(p -nitro benzoyl amino)-benzene sulphonainido] pyridine filtered off, washed with water and dried. Melting point 272".

, Example 8 5.4 grams of 5-amino-8-methoxy-quino1ine is dissolved in 10 cc. ofpyridine, 7.3- grams of'pacetylamino-benzene-sulphonyl chloride added, and the mixture heated at 90 C. for a short time. Water is then added and the precipitated 5-(pacetylamino benzene sulphonamido)-8-methoxy quinoline filtered off and crystallised from dilute alcohol. Melting point 185 C.

0n hydrolysis of this acetyl compound by boiling with 10 parts of 2.N sodium hydroxide followed by neutralisation to Congo red, 5-.(p-aminobenzene-sulphonamido)-8-methoxy quinoline is obtained. which recrystallised from water; melts at 228-230 C. I

Example -9 6.6 grams of 2:6 diamino-pyridine is dissolved in 40 cc. of pyridine and 29.0 grams of p-acetylamino-benzene-sulphonyl chloride added. When the reaction mixture has cooled, water is added and the precipitated 2:6 di(p-acetylamino- Example 10 5 grams of 2-hydroxy-4-methyl-'I-amino-quinoline are suspended in 25 cc. of pyridine, 6.8,grams of p acetylamino benzene sulphonyl chloride added, and the mixture heated on the water bath for a short time. On dilution with water (100 co.) the precipitated 2-hydroxy-4-methyl-7-(pquinoline is precipitated, filtered oil, washed with water andcrystallised from. dilute alcohol. Melting point On hydrolysis of this compound by boiling air 1 hourrwith 10 parts of dilute caustic soda and. subsequently acidifying with dilute acetic acid 2' hydroxy-4 methyl 7-(p-amino-benzene-sulphonamido) -quinoline isprecipitated. After purification by solution in hot dilute sodium hydroxide and re-precipitation by acidifying with hot acetic acid the pure compound melts at'289 C.

7 Example 11 14 gramsof 2 amino-.pyridine-ii-carboxylic acid is suspended in 100 cc. of pyridine and 24 grams of p-acetyl-amino-benzene sulphonyl chloride added. The mixture is heated on the water bath for 10 minutes,.diluted withwater, and the precipitated 3 carboxy-2- (p-acetylamino benzenesulplionamido) -pyridine recrystallised from al- 001101. M. 191L175? C. (doc), On hydrolysis by .aasaaaa suspended in 2000. of pyridine, 23.5 grams of pacetylamino-benzene-sulphonyl chloride added,

and the' mixture heated on the water bath for 10..

minutes. On dilution'wi'th water crude B-methyl- 2 --(p-acetylamino-benzene sulphonamido) pyridine separates and is collected and after crystallisation from dilute acetic acid melts at 215 C.'

It is boiled with 150 cc. of 2N sodium hydroxide solution, filtered, and 150 cc. of 2N acetic acid added, and pure crystalline 6-methyl-2-(pamino-benzene sulphonamido) pyridine thereby precipitated; Melting point 219 C. after recrystallisation from dilute acetic acid.

Example. 13

14 grams of6-aniino-quinoline are dissolved in 30 cc. of quinoline and24 grams of p-acetylamino-benzene-sulphonyl chloride added. The

mixture isheated on a steam bath for about 30 minutes and diluted with 300 cc. of water when 6- (p-acetylamino-benzene sulphonamido)-quinoline is precipitated, filtered oil, washed with water and recrystallised. Melting point 275 C. On hydrolysis with ten parts of boiling 2N caustic soda solution for 1 hour and acidifying with dilute acetic acid 6-(p-amino-benzene-sulphonamido) -quinoline is obtained. After crystallisa-' tion from dilute alcohol it melts at 200 C.

-Example 14 4.7 grams of 2-amino pyridine are dissolved in 20 cc. of benzene, 12 grams of p-acetylamino-benzene-sulphonyl chloride added and the mixture allowed to stand. The solid which separates is filtered oil and boiled for 1 hour with 90 cc. of 2N caustic soda solution. n acidification with dilute acetic acid 2-(p-amino-benzene sulphonamido) -pyridineis precipitated and recrystallised from acetone. -Melting'point190"C.

Example 2 grams of 2-(p-chlor-benzene-sulphonamido)- pyridine (Example 4) or 2 grams of 2-(p-bromsimilar manner from p-brom-benzene-sulphonylchloride and 2 amino-pyridine) i heated in a melts at 240 C.

tion of percent. acetic acid. Melting point Example 17 5 grams of 2-(p-chlorbenzene-sulphonamido)- pyridine are heated in a closed vessel with 20 cc. of a 30 per cent. aqueous solution of dimethylamine and 0.25 gram of cuprous chloride at 170 C. for 12 hours. After cooling, the contents of the tube are diluted with water and the precipitate extracted with cold dilute hydrochloric acid.

Sodium acetate is then added to the acid extract and the precipitated 2-(p-dimethylamino-benzene sulphonamido)-pyridine recrystallised from alcohol. It melts at 218-220 C.

Example 18 15 grams of '4-amino-pyridine are dissolved in 80 cc. of water, 40 grams of p-acetyl-amino-benzene-sulphonyl chloride added followed. by 10 grams of anhydrous sodium carbonate. 'I'he mixture is stirred at room temperature for 1 hour and the precipitated 4- (p-acetylamino-benzene sulphonamido) -pyridine filtered oil. and washed with water. Crystallised from alcohol it melts at 252 C. Hydrolysis by boiling with 400 cc. of 2N caustic soda solution for 1 hour and acidifying the-resulting solution with dilute acetic acid gives 4 (p amino-benzene sulphonamido) pyridine which on recrystallisation from dilute alcohol Example 19 21.4 grams of p-acetylamlno-benzene-sulphonamide,. 13.5 grams of potassium carbonate, .1.0 grams of copper powder and 16.4 grams of 2.- .chloro-quinoline are heated together underreflux-for 1 hours at 240-250 C. The cooled reaction mass is extracted with boiling water filtered and the filtrate acidified with acetic acid when crude 2-(p-acetylamino-benzene-sulphonamido) quinoline is precipitated.

On hydrolysis by boiling with 160 cc. of 2N sodium hydroxide for 1 hour and acidifying the which after re-solution in boiling dilute alkali resulting solution with acetic acid z-(p-aminobenzene-sulphonamido) quinoline is obtained and acidifying with hot acetic acid is obtained crystalline. Melting point 193-195 C.

Example 20 17 grams of 2-(p-dimethylaminobenzene-sulphonamido)-pyridine (Example 17) is dissolved benzene-sulphonamido) pyridine (obtained in a closed vessel with 8 cc. of a 30 per cent aqueous solution of methylamine, and 011 gram of cuprous chloride for 12 hours at 150 C. After cooling. the reaction mixture is diluted with water and the precipitated 2(p-"rnethyl-amino-benzene-sulphonamido) pyridine purified by recrystallisation 'from alcohol. Melting point 154 0.

Example 16 I 9 grams or 2:4 dinitro-diphenylamino-fl-sul phonyl chloride prepared by the action of phosphorous pentachloride on the sodium 'salt of the corresponding sulphonic acid is added to a solution of 2.3 grams of 2-amino-pyridine in. 20 cc. of

pyridine. when the reaction is complete. water "is added and the precipitated 2-(p-'(2:4 dinitrophenylaminol benzene sulphonamido) -pyridine filtered oil, washed, and crystallised from its so 'lution in hot dilute alcoholic caustic soda by addiin 60 00. of 2N sodium hydroxide solution, and 7 grams of dimethyl sulphate added with stirring to the cooled solution. 2- (p-dimethylamlno-benzene-sulphonmethylamido) pyridine separates as an oil which rapidly solidifies and when recrystallised from dilute acetic acid melts at 155 C.

Example 21 20 grams of .2-(p-amino-benzene-sulphonamido)'-pyridine is dissolved in 120 cc. of 2N sodium hydroxide solution and 8 cc. of dimethyl sulphate are added. After shaking for 30 minutes the precipitated 2-(p-amlno-benzene-sul- 'phonmethyl amido) pyridine is filtered ofl,

washed with waterand crystallised from alcohol. It melts at 225 C. l

Example 22 9 .6 grams of 6 aminoquinaldine is dissolved I in 27 cc. of pyridine and 11.8 grams of p-nitrobenzene-,sulphonic-acid-anhydride added. When the reaction is complete about 500 cc. of water is added and the precipitated's-(p-nitro-ben- I .chloride are suspended zene sulphonamido) quinaldine is filtered ofl and washed with water. I

On reduction withferrous hydroxide as described in Example 3,\6- (p-amino-benzene-sulphonamido)-quinaldine, melting point 252 C., is obtained. Example 23 6.4.grams of 2-amino-pyridine is dissolved in 50 cc. of pyridine and 22 grams of p-acetylbenzyl amino benzene 'sulphonyl chloride (British Patent 483,945) is "added. When the reaction is complete the mixture is diluted with water and filtered, and the residual 2- (p-acetylbenzyl-amino-benzene-suiphonamido) crystallised from alcohol. Melting point 177" C. The acetyl compound on boiling with 30% sodium hydroxide solution for 12 hours and aciditying with acetic acidyields Z-(p-benzylaminobenzene-sulphonamidol' pyridine which after recrystallisation from alcohol melts at 200.

Example 24- l/ 9.7 grams of 1 amino-isoquinoline is dissolved in 20 cc. of pyridine and 16 grams of p-acetylamino-benzene-sulphonyl chloride added, the temperature being kept below 50 C. when the reaction is complete, water is added and the solid separated by filtration. After purification by dissolving in aqueous alcoholic sodium. hydroxide solution and precipitation by acidifying with acetic acid, crystalline. 1-(p-acetylamlno-benzene-sulphonamido)-i soquinoline, melting point 225 c. is obtained.

. The acetyl compoundon hydrolysis with parts of boiling 2N sodium hydroxide solution for 1 hour, followed by acidification with acetic acid gives 1- (p-amino benzene sulphonamido) -isoquinoline. Melting point 263 C.

Example 25 Example 26 7 grams of p-diethylamino-azobenzene-p-sul- 'phonyl chloride (prepared by the action of phosphorus pentachloride on sodium p-diethylaminoazo-benzene sulphonate) is added to 1.9 grams of z-aminoqpyrldine dissolved in cc; of pyridine and aiter the reaction is over water is added. The precipitated 2- (p-diethylaminoazobenzenep-sulphonamido)-pyridirie is filtered ofl, washed with water, and dissolved in 5 parts of 2N sodium pyridine melts at 225 C.

water is added. To the mixture is added 2 grams of anhydrous sodium carbonate and the whole vigorously shaken at room perature for 1 hour. The mixture is diluted wi 20 cc. of water. the chloroform layer together with any undissolved solid separated 011 and the chloroform removed, by distillation. The residue is boiled with 25 cc. of 2N sodiumhydroxide for- 30 minutes and the solution precipitated by addition of hot glacial acetic acid until acid to litmus. The

crystalline precipitate oi 2-(p-amino-benzenesulphonamido)-pyridine is filtered of! and recrystallised irom acetone. It melts at 189-190 C.

- Example 28 A mixture of 4.6 grams of p-acetylaminobenzenesulphon-methylamide, melting point 183 (3., (obtained by the interaction of p-acetylaminobenzene-sulphonyl chloride and aqueous I methylamine) 3.2 grams' oi 2-bromopyridine, 2.8 grams of potassium carbonate and 0.2 grams 0! copper powder is heated at 200 C. for 1 hour. The cooled melt is extracted with acetic acid and the filtered extract is concentrated whereupon z-(p-acetylamino benzene sulphon methylamido)-pyridine separates. Crystallised from dilute acetic acid, it melts at 231 C. Hydrolysis by boiling for 1 hour with 10 parts of 2N sodium hydroxide gives on acidification with acetic acid 2-(p-amino-benzene-sulphon-methylamido) -pyridine. crystallised from alcohol it Example 29 25 grams of phenyl- 2-a.mino-pyridine-5-sulphonic acid is suspended in cc. of pyridine and '24 grams of p-acetylamino-benzene-sulphonylchloride is added. After heating on a steam bath for 15 minutes, the mixture is diluted with 500 cc. of water and the precipitated phenyl-Zipacetylamino-benzene-sulphonamido) -pyrldine-5- sulphonate is collected. crystallised from 50% acetic acid it melts at 175-185" C.

hydroxide solution. The solution is warmed to 30-40 C. "and solid sodium hydrosulphite added gradually until the red colour or the solution is discharged. Acetic acid is then added until the solution is faintly acid; on concentration 2-(pamino-benzene sulphonamido) pyridine separates, and is Purified by recrystallisation from 7 alcohol. Melting point 190. 0.

Example 27 3' grams of p-acetyl-amino-benzene sulphonyl 1 gram or 2 amino-pyridine dissolved in 5 cc. of

in 5 cc. of chloroform and This ester on boiling for 1% hours with ten times its weight 01 2N sodium hydroxide solution and addition, with cooling, of hydrochloric acid until just acid to Congo red gives Z-(p-aminobenzene sulphonamido) pyridine 5-sulphonic acid. Melting point 305 C.

Example 30 9.4 grams of 2 amino-pyridine is dissolved in cc; of acetone and 11.6 gramsof p-acetylamino-benzene-sulphonyl chloride is added. The mixture is boiled under reflux for 1 hour, the

acetone removed by distillation and the residue.

treated with water. The 2-(p-acetylaminobenzene-sulphonamido)-pyridine so formed is collected. It melts at 224C. when crystallised from aqueous alcohol.

Example 31 To 9.4 grams of 2-amino-pyridine at 55 C. is added 11.6 grams of p-acetylamino-benzenesulphonyl chloride. When the reaction is over the' melt is dissolved in cc. of 2N sodium hydroxide solution and the mixture is boiled under reflux for 1 hour. Acidification with acetic acid precipitates 2(p-amino-benzene-sulphonamido)- pyridine which melts at C. when from aqueous alcohols Example 32 A mixture 0215.8 grams of 5-nitro-2-chloropyridine, 21.4 grams of p-acetylamino-benzcne sulphonamide, 13.5 grams of potassium carbonate crystallised heated for 30 minutes at 180 c. The mixture is extracted with boiling water and filtered; acidification of the filtrate with acetic acid then gives 5 nitro 2 (p acetylamino-benzene sulphona- 5 mido-pyridine. Melting point 264 C.

Example 33 To a solution of 2.2 grams of 5-iodo-2-aminopyridine in 7 cc. of pyridine is added 2.4 grams 1 of p acetylamino benzene sulphonyl chloride. When the reaction is over 70 cc. of water are added and the precipitate of 5-iodo-2-(p-acetylamino benzene sulphonamido) -pyridine is collected, washed with water and crystallised from 1 50% acetic acid. Melting point 234 C. Hydrolysis of this with 10 parts of 2N sodium hydroxide solution by boiling for 1 hour under reflux followed by addition of excess of 2N acetic acid pyridine. Purified by solution in boiling aqueous alcoholic sodium hydroxide followed. by addition of boiling dilute acetic acid, it melts at 219 C.

Example 34 acetylamino-benzene-sulphonyl chloride is added.

When the reaction mixture has cooled,-100 cc. of

methylamido) -pyridine (Example 21) is dissolved in 100v cclof 2N-hydro-chloric acid and 10 cc. of acetic anhydride followed by suflicient saturated sodium acetate solution to remove Congo red acidity are added. The precipitate of 2-(pacetylamino benzene sulphonmethylamido)- pyridine is collected, washed and crystallised from dilute acetic acid. Melting point 231 C.

What we claim and desire to secure by Letters Patent is: y

l. The preparation of compounds of the class consisting of p amino benzene-sulphonamidopyridine and quinoline derivatives by the action of a benzene sulphonamide containing, in the para position, a substituent capable of conversion into an amino group, such substituent being a member of the class consistingof an acylamino group convertible to an amino group by hydrolysis, a nitro group convertibleby reduction, gives 5-iodo-2-(p-aminobenzene-sulphonamido)- 2o water are added and the precipitate of crude 2- 30 (p acetylamino-benzene sulphonmethylamido) pyridine is collected, washed and crystallised fromdllute acetic acid. Melting point 231 C.

' Example 35 v t 3 10 grams of 2 (p aminobenzene sulphonan azo group convertible by reduction, and a halogen convertible by the'action of ammonia, on a member of the class consisting of pyridine and quino'line compounds containing a reactive halogen substituent on the nucleus of that member.

2. In the process according to claim 1, the step which comprises reacting the said para-substituted benzene sulphonamide with the said member of the class consisting of pyridine and quinoline compounds containing a reactive halogen substituent on the nucleus of that member in the presence of potassium carbonate and copper.

ARTHUR JAMES EWINS.

MONTA GUE ALEXANDER PHILLIPS. 

